Development of effective vaccines against respiratory viruses requires a thorough understanding of the immunological response to individual proteins. We have chosen two viruses, influenza virus type A and respiratory syncytial (RS) viruses for detailed analysis. Individual recombinant vaccinia viruses that express the ten influenza virus genes have been constructed. Mice vaccinated with the vaccinia/influenza hemagglutinin recombinant made neutralizing antibodies and are protected against lower respiratory infection with influenza virus; however, the protection is subtype specific. Recombinants that express the nucleoprotein elicit a cross-reactive cytotoxic T cell response, but mice are not protected against infections. Evidence that humans also make cross-reactive cytotoxic T cells directed against the influenza nucleoprotein was demonstrated by infecting autologous human peripheral blood lymphoblastoid cells with recombinant vaccinia viruses. Recombinant vaccinia viruses that express the RS F and G proteins have been constructed. The proteins synthesized by the recombinants are glycosylated and transported to the plasma membrane. Cotton rats that are vaccinated with either recombinant produce neutralizing antibodies and are protected against lower respiratory infection with RS.